Hiroshi Egami

Elevation of circulating interleukin 6 after surgery: Factors influencing the serum level

To investigate the effect of surgical trauma and other factors on the postoperative elevation of serum interleukin 6 (IL-6), we examined changes in IL-6 concentration after major thoracoabdominal surgery. Serum IL-6 levels reached the maximum concentration on the first postoperative day in all 38 patients, with peak ranging from 1400.8 +/- 383.4 pg/ml (mean +/- SEM) to 29.8 +/- 3.8 among six groups who underwent surgery at different sites. The IL-6 peak was significantly correlated with surgical trauma as defined by the operation length and the volume of blood loss during surgery (r = 0.554, P < 0.01 and r = 0.427, P < 0.01, respectively). The peak concentration of serum IL-6 in patients undergoing esophagectomy was significantly higher than in those undergoing pancreaticoduodenectomy (P < 0.05), despite a similar degree of surgical trauma defined by the operation length and volume of blood loss during surgery. Peak IL-6 concentration observed in a patient who underwent esophagectomy was about 100-fold greater in fluid drained from the thorax than in the peripheral blood. IL-6 mRNA was demonstrated in leukocytes from thoracic and abdominal exudate at 6, 24 and 48 h after surgery. In contrast, IL-6 mRNA could not be detected in leukocytes from the peripheral blood. Similar findings were also observed for interleukin 8 (IL-8). However, interleukin 1 beta (IL-1 beta) and tumour necrosis factor-alpha (TNF-alpha) were detected only once after surgery in the drainage fluid.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship between plasma cytokine concentration and multiple organ failure in patients with acute pancreatitis.

The dynamic aspects of circulating cytokines and cytokine modulators and their relationship with development of multiple organ failure (MOF) in patients with acute pancreatitis were analyzed. All cytokine and C-reactive protein levels in the circulation were higher than those in the MOF group. In particular, plasma concentrations of soluble tumor necrosis factor receptors (sTNF-RI and sTNF-RII) were significantly higher in patients with MOF than in those without even at admission. Furthermore, plasma concentrations of sTNF-Rs and interleukin-1 (IL-1) receptor antagonist (IL-1ra) were much higher than those of their counterparts, TNF-&agr; and IL-1&bgr;, respectively. These results suggest that the plasma concentrations of sTNF-Rs are useful predictors for the development of MOF, and actions of TNF-&agr; and IL-1&bgr; could be regulated by their modulators (soluble receptor and receptor antagonist, respectively) in the pathologic condition of severe acute pancreatitis.

No-touch isolation technique reduces intraoperative shedding of tumor cells into the portal vein during resection of colorectal cancer

BACKGROUND The mutant-allele-specific amplification (MASA) method is capable of detecting 1 genetically altered tumor cell among thousands of normal cells. The MASA enabled us to detect occult tumor cells undetectable by histopathologic examination of lymph nodes and blood samples. METHODS To investigate whether tumor manipulation during operation enhances cancer cell dissemination into the portal vein with use of MASA and to assess the effect of the no-touch isolation technique in the treatment of colorectal cancers, 27 colorectal cancers (17 were operated on conventionally and 10 were operated on according to the no-touch isolation technique) were screened for mutations in K-ras or p53. We next examined blood samples of the portal vein collected before, during, and after manipulation of tumors, using MASA to look for the specific mutation found in the primary tumors. RESULTS Somatic mutations were identified in 18 of these primary tumors (11 were in the conventional resection technique group and 7 were in the no-touch isolation technique group). In 8 of 11 (73%) conventional resection technique cases, we identified the same genetic alteration of the primary tumor in the portal blood during operation, whereas only 1 patient (14%) in the no-touch isolation technique group had a positive result. CONCLUSIONS The no-touch isolation technique may be useful to prevent cancer cells from being shed into the portal vein during surgical manipulation.

Patterns of growth and metastases of induced pancreatic cancer in relation to the prognosis and its clinical implications

To understand high malignancy of pancreatic cancer, the growth and metastatic patterns of pancreatic cancer induced in Syrian hamsters were examined. In this model, induced tumors resemble the human disease morphologically, clinically, biologically, and immunologically. In the current study, primary-induced cancer and transplants of pancreatic cancer cell line (PC-1) into the SC tissue or pancreas of homologous hosts were used. In the primary-induced pancreatic cancer, perineural invasion was the most common path (88%), followed by lymphogenic (31%) or vascular (2%) metastases. Inoculation of PC-1 cells into the pancreas resulted in 100% tumor take within 3 weeks. Of 19 intrapancreatic allografts, all showed peritoneal invasion, 5 (26%) liver metastases, 3 (16%) lymph node metastases, 17 (89%) perineural invasion, and none vascular invasion. Even microscopic tumors were found to metastasize primarily via perineural spaces. It was also demonstrated, for the first time, that cancer cells take this route to reach distant tissues, including the lymph nodes. Intraductal spreading occurred in both primary cancers and intrapancreatic allografts either continuously or discontinuously. The patterns of discontinuous intraductal tumor expansion imitated tumor multicentricity. Although perineural invasion was the most common feature of primary cancer and intrapancreatic allografts, lymphatic, hepatic, and vascular invasion and metastases usually occurred in advanced cases. Environmental factors seem to influence expansion and metastases, as evidenced by differences in growth and in metastatic patterns between SC and intrapancreatic allografts.

Evaluation of Serum CA125 Values in Healthy Individuals and Pregnant Women

CA125 is an antigenic determinant associated with human epithelial ovarian carcinoma. This study was undertaken to evaluate the distribution of serum CA125 levels and the effect of smoking on these levels among healthy individuals and clarify the relation of maternal serum CA125 level and pregnancy. Among 552 healthy individuals, the distribution of serum CA125 values was demonstrated to resemble logarithmic normal distribution. Analysis of variance about age and sex revealed apparent elevation of values for women under 49 years of age in comparison with those for women over 50 years of age and men. Values for these two groups were 143 units/ml for the former and 32 units/ml for the latter, with a 99.7% confidence limit. These values exclude 99.3% of the former and 99.7% of the latter. Serum CA125 values were not affected by smoking. The measurement of serum CA125 levels in 71 pregnant women disclosed a significant elevation during the first trimester in comparison with non-pregnant women under 49 years of age. These results indicate that CA125 values must be deliberatively evaluated in young women, especially during first trimester of pregnancy.

Clinical Significance of Serum CA125 Values in Patients with Cancers of the Digestive System

A study of 347 patients with gastrointestinal diseases revealed elevation of CA125 in sera of 63% of patients with pancreatic carcinoma, 46% of patients with carcinoma of the biliary tract, 40% of patients with liver carcinoma and 11–37% of patients with other carcinomas. All of the patients with acute pancreatitis, chronic pancreatitis, cholelithiasis, and peptic ulcer had normal CA125 values, but 35% of patients with liver cirrhosis and 10% of patients with chronic active hepatitis had elevated values. Patients with disseminated carcinomas had significantly higher levels than patients with localized carcinomas. CA125 did not significantly correlate with CA19–9 or carcino-embryonic antigen in patients with pancreatic carcinoma. Ninety-seven percent of patients with pancreatic carcinoma were defined as being positive when both serum CA125 and CA19–9 were evaluated. These results indicate that CA125 is useful for differentiating pancreatic carcinoma from chronic pancreatitis, especially when supplemented with CA19–9.

The role of tumor necrosis factor-α in the aggravation of cerulein-induced pancreatitis in rats.

SummarySevere acute pancreatitis is often complicated by intraperitoneal infection, resulting in multiple organ failure (MOF). It is known to elevate serum tumor necrosis factor (TNF-α) in patients with sepsis and/or MOF. In order to study the role of TNF-α in the aggravation of acute pancreatitis, we investigated TNF-α production by peritoneal macrophages in acute pancreatitis rat using the cerulein-induced pancreatitis model. TNF-α production by isolated peritoneal macrophages following lipopolysaccharide (LPS) stimulation was significantly increased in pancreatitis rats as compared with nonpancreatitis control rats (p<0.001). Serum TNF-α activity was elevated following intraperitoneal administration of LPS as the septic challenge both in pancreatitis rats and in control rats, being significantly higher in the former (p<0.05). Histological findings and liver function tests revealed that LPS induced more severe liver damage in pancreatitis rats than in control rats within 24 h after LPS administration. These results indicate that increased TNF-α production by peritoneal macrophages in acute pancreatitis augmented LPS-induced liver injury and suggest the possibility that TNF-α may play a role in the development of MOF during acute pancreatitis complicated by intraabdominal sepsis.

Immunohistochemical localization of group II phospholipase A2 in human pancreatic carcinomas.

SummaryThe immunohistochemical localization of group II phospholipase A2 (PLA2) in normal fetal and adult human pancreases, 5 chronic pancreatitis, and 30 pancreatic ductal carcinomas was investigated. Furthermore, pancreatic carcinoma cases were correlated with histologic type, tumor size, vascular involvement, lymphatic involvement, perineural invasion, lymph node matastasis, amount of interstitial tissue in the tumor, growth pattern of the tumor, and clinical stage. In the normal pancreases, almost all of acinar cells and a few cells of small and large ducts were immunoreactive in a supranuclear pattern. In chronic pancreatitis, immunoreactivity was retained in several acini, islet cells, and ductal cells, but the staining was diminished in acinal cells of atrophic lobules. A strong immunoreactivity was found in the cells of hyperplastic ducts. In pancreatic ductal carcinomas, the immunoreactivity was observed in 25 cases (83%). Eighteen of 25 (72%) immunoreactive cases showed a cytoplasmic granular or luminal surface pattern, both of which were not observed in the normal pancreas. Among the clinocopathological parameters of pancreatic cancer, the incidence of expression of this enzyme was significantly higher in infiltrative type cancers than in expansive and localized tumors. Furthermore, the expression of group II PLA2 was significantly higher in the tumor with larger amount of interstitial tissue than in that with smaller amounts of interstitial tissue. These results suggest that expression of group II PLA2 in human pancreatic ductal carcinomas is possibly involved in the proliferation of interstitial tissue directly or indirectly through prostaglandin production.

Interleukin-8 is constitutively and commonly produced by various human carcinoma cell lines

SummaryWe examined the production of interleukin-8 and interleukin-6 by 30 human carcinoma cell lines. Serum levels of interleukin-8 were measured in 14 patients with hepatocellular carcinoma by enzyme-linked immunosorbent assay and Northern blotting. Furthermore, serum interleukin-8 was also investigated in a nude mouse bearing a tumor of the HuH7 hepatoma cell line producing interleukin-8. Of the 30 cell lines, 29 (96.7%) constitutively produced interleukin-8, and 19 of the 29 (65.5%) were high producers (>1 ng/ml culture supernatant). Among the high producers, 4 cell lines released both interleukin-8 and interleukin-6. Interleukin-6 was constitutively produced by 17 of the 30 (56.7%) cell lines, 4 of which (23.5%) were high producers (>1 ng/ml). By Northern blot analysis, mRNAs of interleukin-8 and interleukin-6 were detected in producing cell lines. Of 14 patients with hepatocellular carcinoma, 4 (28.5%) showed increased levels of serum interleukin-8. Furthermore, inoculation of the HuH7 hepatoma cell line which produced the highest amount of interleukin-8 into a nude mouse resulted in tumor production accompanied by an elevated level of human interleukin-8 (646 pg/ml) in the peripheral blood. Thus, interleukin-8 is constitutively and commonly produced by various carcinoma cell lines. The production of interleukin-8 by carcinoma cells may be related to the elevation of serum interleukin-8 in patients with hepatocellular carcinoma. Finally, these cell lines may be valuable for studying the relationship between interleukin-8 and cancer.

The potential role of DFNA5, a hearing impairment gene, in p53-mediated cellular response to DNA damage

AbstractThe tumor suppressor p53 plays a crucial role in the cellular response to DNA damage by transcriptional activation of numerous downstream genes. Although a considerable number of p53 target genes have been reported, the precise mechanism of p53-regulated tumor suppression still remains to be elucidated. Here, we report a novel role of the DFNA5 gene in p53-mediated etoposide-induced cell death. The DFNA5 gene has been previously reported to be responsible for autosomal-dominant, nonsyndromic hearing impairment. The expression of the DFNA5 gene was strongly induced by exogenous and endogenous p53. The chromatin immunoprecipitation assay indicated that a potential p53-binding sequence is located in intron 1 of the DFNA5 gene. Furthermore, the reporter gene assay revealed that the sequence displays p53-dependent transcriptional activity. The ectopic expression of DFNA5 enhanced etoposide-induced cell death in the presence of p53; however, it was inhibited in the absence of p53. Finally, the expression of DFNA5 mRNA was remarkably induced by gamma-ray irradiation in the colon of p53(+/+) mice but not in that of p53(−/−) mice. These results suggest that DFNA5 plays a role in the p53-regulated cellular response to genotoxic stress probably by cooperating with p53.